Calcium in nerve cells plays an important role in transferring signals between the nerve cells. There are several channels for calcium. However, when a terminal stimulus is transferred thereto, a voltage-dependent Ca2+ channel works primarily. That is, the voltage-dependent Ca2+ channel as a membrane protein regulates various intracellular functions (e.g., muscle contraction, neurogenesis, synapse plasticity, secretion of neurotransmitter and hormone, gene expression, etc.) by controlling an inflow of calcium ion from a cell exterior.
The voltage-dependent Ca2+ channel can be functionally classified into two groups depending on its biophysical property: a low voltage-activated Ca2+ channel (hereinafter referred to as “LVA”), which is activated at lower voltage; and a high voltage-activated Ca2+ channel (hereinafter referred to as “HVA”), which is activated at higher voltage. The HVA calcium channel is subdivided into L-, P/Q-, N- and R-types depending on a pharmacological property of the current induced thereby The LVA calcium channel is characterized by small conductivity being very quickly activated and inactivated. Thus, it belongs to T (transient)-type calcium channel (Tsien, R. W. et al., Trends Neurosci. 1988, 11, 431-438).
It has been reported that the T-type calcium channel is involved in bursting firing of nerve cells (Huguenard, J. R. et al., Annu. Rev. Physiol. 1996, 58, 329-348), pacemaker activity of the heart (Zhou, Z. et al., J. Mol. Cell. Cardiol. 1994, 26, 1211-1219), secretion of aldosterone (Rossier, M. F. et al., Endocrinology 1996, 137, 4817-4826), fertilization (Arnoult, C. et al., Proc. Natl. Acad. Sci. 1996, 93, 13004-13009) and pain relief (Ikeda, H. et al., Science 2003, 299, 1237-1240).
The T-type calcium channel may become over-expressed due to genetic or environmental causes, such as epilepsy (Tsakiridou, E. et al., J. Neurosci. 1995, 15, 3110-3117), high blood pressure (Self, D. A. et al., J. Vacs. Res. 1994, 31, 359-366), ventricular hypertrophy (Nuss, H. B. et al., Circ. Res. 1995, 73, 777-7825), pain (Shin, H. S. et al., Science 2003, 302, 117-119), and angina pectoris (Van der Vring, J. A. et al., Am. J. Ther. 1999, 6, 229-233). It has been found that there are three types of genes, α1G, α1H and α1I, in the T-type calcium channel through gene cloning techniques (Talley, E. M. et al., J. Neurosci. 1999, 19, 1895-1911). There have been numerous attempts to develop a blocking agent, which selectively inhibits the T-type calcium channel. However, there were no effective T-type calcium channel blockers except for Mibefradil and ZD7288 (Felix, R. et al., Biochem. Biophys. Res. Commun. 2003, 311, 187-192). Accordingly, by developing a selective T-type calcium channel blocker, it may be possible to develop an epochal treating agent for epilepsy, high blood pressure and pain-related diseases.
A representative drug for blocking the T-type calcium channel is Mibefradil of Hoffman La Roche Ltd. (registered trademark: Posicor). The drug was found to be effective in treating high blood pressure, angina pectoris and cerebral apoplexy. It has been placed in the market as a treating agent for high blood pressure since May of 1997. However, a side effect caused by a drug-drug interaction due to inhibition of CYP 3A4 hepatic enzyme was discovered. As such, the drug was withdrawn from the market on June of 1999, which was just 13 months from first entering the market.
Accordingly, there has been a need in the art to develop a selective T-type calcium channel blocker, which has a new structure that can substitute Mibefradil.